CA1313376C - Lipoxygenase enzyme inhibitors - Google Patents
Lipoxygenase enzyme inhibitorsInfo
- Publication number
- CA1313376C CA1313376C CA000534042A CA534042A CA1313376C CA 1313376 C CA1313376 C CA 1313376C CA 000534042 A CA000534042 A CA 000534042A CA 534042 A CA534042 A CA 534042A CA 1313376 C CA1313376 C CA 1313376C
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- Prior art keywords
- alkyl
- branched
- straight
- compound
- naphthyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
- C07D215/60—N-oxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Abstract
LIPOXYGENASE ENZYME INHIBITORS
Abstract of the Disclosure The present invention is concerned with organic compounds which inhibit lipoxygenase enzymes.
Hydroxy quinol-1-one and quinol-2-one based compounds found to be potent inhibitors of 5-. 12-, and 15-lipoxygenase enzymes. The present invention also relates to method of making such compounds, and to methods of inhibiting lipoxygenase enzymes inhuman and animal hosts in heed of such treatment.
Abstract of the Disclosure The present invention is concerned with organic compounds which inhibit lipoxygenase enzymes.
Hydroxy quinol-1-one and quinol-2-one based compounds found to be potent inhibitors of 5-. 12-, and 15-lipoxygenase enzymes. The present invention also relates to method of making such compounds, and to methods of inhibiting lipoxygenase enzymes inhuman and animal hosts in heed of such treatment.
Description
13~33~6 LIPOXYG~LASEENZY~I~ ORS
Technical~Field This inuention relates to organic compounds which inhibit lipoxygenase enzymes. It also relates to methods of making such compounds, and to methods of inhibiting lipo~ygenase enzymes in human and animal hosts in need of such treatment.
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase conuerts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LTs).
Similarly 12- and 15-lipoxygenase, conuert arachidonic acid to 12- and 15-HPETE respectiuely. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-~P~TE
, is the precursor of the class of biological agents known as the lipoxins.
~ uariety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they haue been implicated as mediators in ~arious disease states. For example, the LTs C4 and D4 are potent constrictors of human airways ~n uitr_ and aerosol administration of these substances to non-asthmatic uolunteers induces broncho constriction. LTB4 and S-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also haue been found in the synouial fluid of rheumatoid arthritic patients. The biological actiuity of the LTs has been reuiewed by Lewis and ~ustin (J. Clinical Inuest. ~3, 889, 1984~ and by Sirois (~d~. Lipid Res. 21, r/8, 1985).
Bl The product 12-HElE has been found in high le~els in epidermal tissue of patients with psoriasis.
The lipoxins ha~e recently been shown to stimulate elastase and superoxide ion release from neutrophils.
Thus, lipoxygenase enzymes play an important role in the biosynthesis of mecdiators of asthma, allergy, arthritis, psoriasis, and in-flammation.
Blocking these enzyrnes interrupts the biochemical pathways in~ol~ed in these disease states.
Background ~rt Relati~ely few compownds are known from the prior ar~ which are inhibitors of the lipoxygenase enzymes. Qmonq the lipoxygenase inhibitors known to the art are: ~-861, a 5-lipoxygenase inhibitor, disclosed in U.S. Patent 4,393,075, issued July 12, 1983 to Terao et al.; pyrazolo pyridines, which are 5-lipoxygenase inhibitors, disclosed in European Patent ~pplication of Irikura et al., S.N. 121,806, published October 17, 1984; arachidonyl hydroxamic acid, a S-lipoxygenase inhibitor, disclosed in E. J. Corey et al., J. ~m. Chem.
Soc., 106, 1503 (1984) ancl European Patent ~pplicati.on of P.H. Nelson, S.N. 104,468, published ~pril 4, 1984;
BW755C, inhibitor of 5- and 12-lipoxygenases, disclosed in Radmark et al., FEBS Lett., 110, 213 (1980);
nordihydroguariaretic acid; an inhibitor of 5- and 15-lipoxygenases, disclosed in Morris et al., Prostaqlandins, 19, (1980); RE~-5901, a S-lipoxygenase inhibitor, disclosed in Coutts, Meeting ~bstract 70, Prostaglandins and _eukotrienes '84, quinoline N-oxides, 5-lipoxygenase inhibitors disclosed in Ewropean patent application of Hashizumo et al., S.N. 128,374, published December 19, 1984 and benoxaprofen, disclosecl in J.
Walker, Pharm. Pharmacol., 31, 778 (1979). It would b~
useful to ha~e compounds which are more po-tent inhibitors of these enzymes.
13~33~
In addition a nulnber of compounds identified as ha~ing sorne lipoxygenase inhibitory acti~ity are structurally related to arachidonic acid. Such compounds are highly swsceptible to oxidation in ~itro and to breakdown by con~entional pathways of lipid rnetabolisrn ln Vl~O. l-hus as well as hauing the desired potency it would be desirable to ha~e agents which are relati~ely simple in structure, and relatiuely resistant to oxidation and metabolism.
It is an object of the present in~ention to pro~ide cornpounds which are highly potent inhibitors of lipoxygenase enzymes.
It is another object of this in~ention to pro~ide cornpounds ha~ing structures which are simpler and more stab].e than prior art compounds ha~ing lipid-like structures.
It is yet another object of this in~ention to pro~ide cornpounds which inhibit lipoxygenase activi-ty in ~J i IJ o .
These and other objects of this invention will be e~ident from the following disclosure.
Disclosure oF the In~ention ____.__ ___ Thc? present i.n~ention pro~ides for compounds and methods of using cornpounds of the formulae I and II
in inhi.biting lipoxygenase enzyme acti~ity:
~M R
R5 ~ N ~ O R5 ~ ,,OM
R4~R1 ~
where R1 through R5 are 1ndependently selected from hydrogen, Cl-C12 alkyl, alkoxy, carboalkoxy, aryl, nitro, hydroxy, halogen; or where Rl-R2, R3-R4, R4-R5 forrn an arornatic Fused ring; and where M is a pharmaceutically acceptable cation, Cl-C12 alkyl, acyl, or trialkyl silyl.
_4_ ~313376 rhe term alkyl ls wsed herein to mean straight and branched chai.n radicals, including, but not limited to methyl, ethyl, n-propyl, isopropy:l, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The term alkoxy is used herein to mean straight and branched chained oxygen ether radica].s, including, but not limited to methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
The term carboalkoxy is used herein to mean straight or branched chain ester radicals appended at the carbonyl carbon, including, but not limited to carbomethoxy, carboethoxy, carboisopropoxy, carbo-tert-butoxy and the like.
The term acyl is used herein to rnean straight or branched chain carbonyl radicals, including but not limited to, -formyl, acet~l, propionyl, butyryl, isobutyryl and the like.
The term aryl is used herein to mean substituted and unsubstituted aromatic radicals, including, but not lirnited to phenyl, l-napthyl, 2-napthyl and the like.
The term aromatic fused ring is used herein to mean substituted and unsubstituted benzene rings fused to the carbon skeleton of I or II.
The term "pharrnaceutical'ly acceptab'le cation"
is used herein to mean hydrogen and the nontoxic cations based on the alka'li and a'lka:line earth metals, such as sodium, lithium, potassium, magnesium, and the like, as well as those based on nontoxic ammonium, quaternary ammoniurn, and amine cations, including, but not limited to, ammonium, tetramethy:lammonium, tetraethylammonium, methyl amine, dimethyl amine, trirnethyl amine, triethyl amine, ethyl amine, and the like.
_5_ ' 1313376 Method _ T_eatment This in~ention also pro~ides a rnethod of treatrnent ot' inhibiting 5-, 12- and/or 15-lipoxygenase acti~ity in a human or lower animal host.in need of such treatment which rnethod comprises administration to the human or lower anirna'l host an amount of a compound of this in~ention eff'ecti~e to inhibit lipoxygenase acti~ity in the host. The compounds of the present in~ention may be adrninistered oral'ly, parenterally or topically in dosage unit formwlations containing con~entional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
The term parenteral as used herein includes subcutar,eous, intra~enous, intramuscular, intrathecal, intraarticular, epidura'l and intraarterial injection or infusion techniqwes, without lirnitation. The term "topically" encornpasses adrninistration rectally and by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose.
Total daily dose of the compounds of this inuention administered to a host in single or di~ided doses may be in amounts, for example, of from O.OOl to 100 rng/kg body weight dai'ly and more usual~y 0.01 to 10 mg/kg/day. Dosage.wnit cornpositions may contain such amounts or such subrnultiples thereof as may be used to make up the daily dose. It wil]. be understood, howe~er, that the specific dose le~el for any particular patient will depend upon a ~ariety of factors including the acti~ity of the specific compound employed, the age, body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
-6- 1~13376 F rmulation of Pharmaceutical Co~ _it.ions T'his in~enti.on also pro~ides for compositions in unit dosage t'orm for the inhibition of 5-, 12-, or 15-lipoxygenase acti~ity in a human or lower animal host in need of such treatment, comprising a compound of this in~ention and one or more nontoxic pharrrlaceuti.cally acceptable carriers, adju~ants or ~ehic:les. 'rhe amount of active ingredient that may be combined with such materials to produce a sing'le dosage-form will vary depencding upon uarious factors, as indicated above.
~ ~ariety of materials can be used as carriers, adjuvants and ~ehicles in the compositions of this in~ention, as a~ailable in the pharmaceutical arts.
Injectable preparations, such as sterile injectable aqueous or oleaginous solutions, suspensions or emulsions, may be formulated according to known art, using suitable dispersing or wetting agents and suspending agents, as needed. The steri.le injectable preparation may employ a nontoxic parenterally acceptable diluent or sol~ent as, for example, sterile, nonpyrogenic water or 1,3-butanediol. ~irnong the other acceptable ~ehicles and sol~ents that may be employed are 5% dextrose injection, Ringer's injection and isotonic sodium chloride injection (as described in the USP/NF). In addition, sterile, fixed oils are conuentiona].].y emp].oyed as sol~ents or suspending media. For this purpose any bland fixed oil may be used, inclucling synthetic rnono-, di- or triglycerides.
Fatty acids such as o'leic acid can also be used in the preparation of injectable compositions.
Suppositories for rectal adminis-tration of the compounds of this in~ention can be prepared by mixing the drug with suitable nonirritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the recturn and release the drug.
-7~ ~3 1~ 37 6 ~olid dosage forms for oral adrninistration include capsules, tablets, pills, troches, lozenges, powders and granu:Les. Ln such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. ~uch dosage forms may also comprise, as is normal practice, pharmaceutical adjuvant substances, e.g., stearate lubricating agents. In the case of capsules, tablets and pills, the dosage forms rnay also comprise bufFering agents. Solid oral preparations can also be prepared with enteric or other coatings which modulate release of the acti~e ingredients.
Liquid dosaye forms for oral administration inclu~e pharmaceutically acceptable emulsions, solutions, suspensior1s, syrups and elixirs containing inert nontoxic diluen-ts commonly used in the art, such as water and alcohol. Such cornpositions may also comprise adju~ants, such as we-tting agents, emulsifying suspending, sweetening; fla~oring and perfuming agents.
~y~_S15 O - .he Compounds Cornpounds of this in~enti.on ha~iny formula I
can be prepared according to the reaction sequence Q
below. Qlthough the sequence illustrates the compound where R is hydrogen, it will be seen from the examples that other compounds of this invention can be prepared in the same manner using the appropriate starting materials.
~ ~H3COOOH ~ ~ 2 I OAC OH
~ ~ H~l ~ ~
-8- ~ 3~3~5 Quinoline (1) is treated with peracetic acid to af-ford quinoline N-oxide (2) which is treated with l~ad tetraacetate to yield l-acetoxyquinol 2~1H)-one (3), The N-hydroxyqwinolone (4) is obtained by heating (3) with 2N HCl.
Compounds of this in~entioll ha~ing formula II
can be prepared according to reac-tion sequencc B below.
~lthough sequence B illustrates the compound where R is hydrogen, it will be seen from the examples that other compounds of this in~ention can be prepared in the salne manner using the appropriate starting materials.
OTBDMS
TBDMSCI~ ~ 2 (CH3)2S ~ OHHo NaOAc~' B 8 OH~ 9 Indanone (5) is con~erted to its corresponding silyl eno'l ether (6) with trimethylsilyl chloride or t-butyldimethylsi.lyl chloride and -triethylarnine or sodium bis-trimethylsilylamide and t-buty'ldimethy'lsilyl chloricle. 070nolysis of (6) followed by a reducti~e work-up with dimethylsulfide yields the a'ldehyde acid (7). Reaction with hydroxylamine affords oxime (8) and then heating yields the 2-hydroxyquinol-1(2H)-one (9).
In addition to the method described above, compounds of this in~ention ha~ing formula II where R
~313376 g and R2 are other than hydrogen can be prepared according to reaction scheme C below.
n o n BuONO ~ ~ N-OH
R NaOCH3 ~ R
Indanone (lO) is treated with n-butylnitrite to give 2-hydroxyquinol-1(2H)--one directly.
rhe following examples further illustrate the synthesis and use of compounds of this invention.
_xample l l-hvdr ~yg _nol-2-(1H ? -one Quinollne N-oxide. Peracetic acid (7.5 mL, 39 mmole, 40%) and quinoline (5 9, 39 mmole) were stirred for 2 hours. Much of the acetic acid was removed from the reaction mi.xture in u_cuo. The resulting residue was dissolved in methylene chloride (50 rnL) and washed twice with saturated soclium bicarbonate solution. Qfter drying ouer MgSO~ the soluent was euaporated and the residue was triturated with ether. The resulting tan solid was col'lected by filtration. This material was carried on without further characterization.
~=~Y~ y~u ~ ) one. The desired material was prepared according to the method of Ochiai and Ohta, Chern ~bstr., 59, 2766, (1963). The crude material prepared as described aboue (approximately 5.5 9) was dissolued in benzene (lOO mL) and CaCO3 (0.50 9, 5.0 mmole) and 'lead tetraacetate (20.0 9, 45.1 mmole) were added. The mixture was refluxed for two hours.
The lead by-products which precipitated were filtered off and rinsed with methylene chloride. The soluent was euaporated in uacu to giue a very dark oil.
Hydrochloric acid (2N, 25 mL) was added and refluxed for 30 minutes. ~ brown solid formed which was isolated by filtrati.on and recrystallized from benzene.
Melting Point: 188C.
Example 2 3 a _ometho~y~ droxyqu _ol-~lH)-one ~ c rbomethoxy_3~2-n _ro~he~yl~-p~E__oate. l'he desired material was prepared according to the method described in J. Chem. Soc., 3462 (1960).
Dimethyl rna.Lonate (5.28 g, 40 mrnole), acetic anhydride (15.08 mL, 160 mL), sodium bicarbonate (5.04 g, 40 mmole), and 2-nitrobenzaldehyde were heated at 100C for 2 hrs. ~fter cooling, the rnixture was diluted with water, extracted into ether and washed with saturated sodium bicarbonate. The solvent was rerno~ed ln uacuo and the residue chromatographed, eluting with 45% ether - in pentane. ~ yellow oi]. (2.7 g) was obtained. It crystallized on standing.
3-Ca bom _h x~-1-hvdrox\/quinol-?(lH)-one. l'he desired material was prepared according to the method found in J._Chem. Soc. C, Y13, (1969). To a water solution (20 mL) of sodium borohydride (0.75 g, 20 mmole) and 10% palladium on charcoal (O.OY5 9) was added a me-thanol solution (20 mL) of the diester prepared as abo~e (2.7 g, 10 mmole). The rnixture was stirred at room temperature f'or thirty minutes and then f'iltered.
The filtrate was acidified with concentrated HCl and the solid which t'ormed was recrystallized ~'rom water to afford 700 mg of fine needles.
~elting Point: 170-171C.
IR (KBr): 3450, 1740, 1708, 1625, 1580, 1304, 792, 755.
Mass Spectrum: 219 (M+), 203, 187, 172, 143, 115.
1~3376 xample 3 3-Bromo-l-hyclrox~/quinol-2 ~ 2 __ Using the method of Example 1, but using 3-brornoquinoline, the desired compound was obtained.
Melting Point: 185-.L86~.
IR (KBr): 3070(br), 1620(s), 1580(s).
Mass Spectrum: 239, 241 (M+); 225, 223, 196, 194.
~m~L
~=e~ Ll~droxvquinol=2(lH~
Using the method of Example 1, but using 4-methylquinoline the desired cornpound was obtained.
Melting point: 187C.
IR (KBr): 1640, 1612, 1590, 970, 780, Mass Spectrwrn: 161 (M+), 134, 116, 105.
Exame~ 5 4-Chloro-6-rnetho~ L_oxy~L__o~ -one Using the method of Example 1, but using 4-chloro-6-methoxyqwinoli.ne, the desired compound was obtained.
Melting Point: 210-215C (dec).
NMR (DMS0-d6): 3.92 (s, 3H), 7.03 (s, lH), 7.29-7.41 (m, 3H).
Mass Spectrurn: 225, 227(M ), 210, 208, 201, 180.
le 6 ~-Nitro-l-hydroxyquinol-2(1H)-one -Using the method of Exarnple 1, but using 5-nitroquinoline, the desired compound was obtairled.
Melting Point: 205C (sublime).
NMR (DMS0-d6): 6.96 (d, lH), 7.84 (t, lH), 7.g7 (d, lH), 8.03 (d, lH), 8.23 (d, lH), 11.83 ~s, lH).
Mass Spectrum: 206 ~M ), 190, 174, 160, 130, .~5 115 1~133~
Example 7 _-Methy1-5--nitro-1-hvdrox~quinol-?(lH)-one Using the method of ~xample 1, but using 6-methyl-5-nïtroquinoline, the desired compound was obtained.
Melting Point: 230C (dec).
NMR (DM~0-d6): 2.35 (s, 3H), 6.87 (d, lH) 7.65-7.88 (m, 3H), 11.76 (s, lH).
Mass ~pectrum: 220 (M ), 203, 186, 175, 157, 145, 128, 115.
~e~
6-Chlor~ roxyquinol-2(1H)-one Using the method of Example 1, but using 6-chloroquinoline the desired compound was obtained Melting Point: 175-177C.
IR (KBr): 1640, 1625, 1420, 820, 812.
Mass Spectrum: 195, 197 (M~); 178, 150, 138, 123, 114 Exarnple 9 6-Meth~ drox~qui~ IH)-one Using the method of Example 1, but using 6-methylquinoline, the desired compound was obtained Melting Point: 201-202C.
:[R (KBr): 3050(br); 1625(br,s); 1580(br,s).
Mass Spectrum: 175 (M~), 158, 146, 130, 118, 103.
Exam~le 10 6-Me~h~ ~1r~quinol-?-~lH)-one Using the method of Example 1, but using 6-methoxyquinoline, the desired compound was obtained.
Melting point: 193-194C.
13~3376 NMR ~CDC13): 3.80 (s, 3H), 6,72 (d, lH, J=9Hz), 7.30 (m, 2H), 7.62 (d, lH, J=9Hz), 7.85 (d, 1H, J=9Hz).
IR (KBr): 1630, 1573, 1250, 1163, 830.
Mass Spectrum: 191(M+), 174, 146, 132, 120, 103.
E am~le 11 6-Nitro~l_h~Lr x~quinol _ ~H)-one Using the method of Example 1, but using 6-nitroquinoline, the desired compound was obtained.
Melting Point: 184-185C (dec).
IR (KBr): 1665, 1620, 1520, 1345, 835.
Mass Spectrum: 206 (M+), l90, 176, 160, 144, 132, 116.
Example 12 6-Phen~l-l-hydroxy~u o ~ -one Using the method of Example l, but using 6-phenylquino:Line, the desired compound was obtained.
Melting Point: 219-220C.
IR (K~r): 1670, 1590, 1571, 1425, 818, 759.
Mass Spectrum: 23Y (M ), 220, 192, 165, 152.
~ le 13 7 Meth~ LU_ ol-_~lH~ e Using the method of Example 1, but using 7-methylquinoline the desired compound was obtained.
Melting Point: 170-172 NMR (DMS0-d6): 2.45 (s, 3H), 6.63 (d, lH), 7.10 (d, lH), 7.5 (s, lH), 7.65 (d, lH), 7.86 (d, lH), 11.30 (d, lH).
IR (KBr): 1640, 1500, 1407, 1163, 855.
Mass Spectrum: 175 (M~), 158, 146, 130, 118, 103.
~31337G
Eæl_ 14 ~ Benzo-1-~ dr~ Lj~5LH)-one Using the method of ~xamp'le 1, but using 5,6-benzoquinoline, the desired compound was obtained.
Me'lting Point: 240C dec, NMR (~MS0--d6): 6.87 (d, lH), 7.55-8.85 Irn, 7H).
~ass Spectrum: 211 (M ), l9S, 182, 166, 154, 139, 127.
~me~
3,4-8enzo-1-h~Lrox~quinol-2~
Using the method of Example 1, but using 3,4-benzoquinoline the desired cornpound was obtained Melting Point: 238-240C dec.
IR (KBr): 3050(br); 1625(s); 1604(s); 1590(s).
Mass Spectrurn: 211 (M+), 195, 166, 140.
ExarnPles l~i - 2 By using the method of Example 1 with the following starting materials, the indicat'ed compounds can be prepared:
Ex. St r_ n~Q~_ate ial P_oduct 16 3-Isopropylquino:Line 3-1sopropyl-1-hydroxy-quinol-2(1H)-one 17 3-Phenylquinoline 3-Phenyl-l-hydroxy-quinol-2(1H)-one 18 3-Chloroquinoline 3-Chloro-l-hydroxy-quinol-2(1H)-one 19 4-Ethylquinoline 4-Ethyl-l-hydroxy-quinol-2(1H)-one 4-Nitroquinoline 4-Nitro-l-hydroxy-quinol-2(1H)-one 21 5-Methylquinoline 5-Methyl-l-hydroxy-quinol-2(1H)-one 22 5-Methoxyquinoline 5-Methoxy-l-hydroxy-quinol-2(1H)-one 23 6-Carbomethoxyquinoline 6-Carbomethoxy-l-hydroxyquinol-2(lH)--one 24 6,7--Benzoquino'line 6,7-Benzo-l-hydroxy-quinol-2(1H)-one 7-Methoxyquinoline 7-Methoxy-l-hydroxy-quinol-2(1H)-one 26 l-Phenylquino:line 7-Phenyl-l-hydroxy-quinol-2~1H)-one Example 27 2-h!~r x~ol~-one l-Trimethvlsilox~indene. Trimethylsilyl chloride (5.7 9, 52.3 mrnole), triethylarnine (11.71 9, 116 mmole), and l-indanone (6.22 9, 47.1 mmole) were dissol~Jed in dimethyl forrnamide (25 mL) and refluxed for 17. hours. ~fter cooling, the mixture was diluted wi-th pentane (50 rnL) and washed four tirnes with saturated sodium bicarbonate. ~fter backwashing the aqueous phase with pentane the organic layers were combined, washecl with cold 2N HCl and cold saturated sodium bicarbonate, then dried ouer MgS04. The sol-lent was e~aporated and the residue distil'led (bp 123-125C).
NMR (CDC13): 0.35 (s, 9H); 3.3 (d, 2H, J=2 Hz); 5.45 (t, lH, J'=2 Hz); 7.2-7.6 (m, 4H).
(~-Ca b_X!/P_ny~taldeh~. Ozone was bubbled through a methanol solution ~25 mL) of the silyl enol ether prepared above (1 9, 4. ~ rnrnole) at -78 .
~fter fi~le minutes the reaction turned blue indicating the end of the reaction. ~f'ter purging with nitrogen, the reaction was quench~d with dimethylsulfide (1 g, 16,1 mmole) and stirred for two hours at 0 . The soluent was e~Japorated and the residue chromatographed (eluting with ether/hexane) to aff'ord 0.5 g of a white s oli d .
NMR (CDC13): 3.2 (d, 2H, J=4 Hz), 5.9 (t, lH, J=4 Hz), 7.0-8.2 (m, 4H) .
Mass Spectrurn: 165, 164 (M+), 147, 136, 118, 90 .
~boxl/phenvl~acetaldeh~e o me. This step was patterned after the method of Robinson, J. ~m. Chem.
Soc., 80, 3443 (1958). The material prepared abo~Je (350 mg, 2.1 mrno'le) was suspended in 5 mL water and heated to clissol~e . Hydroxy'lamine (213 mg, 3.1 mmole) and sodium acetate (254 rng, 3.l mmole) were added and the rnixture was heated for 15 minutes. ~fter cooling a solid precipitated which was recrystallized from nitromethane to afford 145 mg of a white solid. This was carried on without characterization.
_~L roxy=gLu nol-1(2H~_one. The material (140 mg, 0.8 mmole) prepared above was dissolved in xylene and heated to 130 for three hours. Upon cooling a yellow solid precipitated which was recrystallized from nitromethane to afford a tan solid (70 mg).
Melting Point: 187-188C.
NMR (DMS0-d6): 6.62 (d, lH), 7.47-7.80 (m, 4H), 8.25 (d, 1H).
IR (KBr): 3100(br), 1640(s), 1612(s), 1585(s), 780.
Mass Spectrum: 161 (M~), 134, 116, 105, 89.1 Ex_~___28 2,3-Di~L_r~ ulnol--_(2H2-one.
Sodium carbonate (5.3 g, 0.05 rno'le) and hydroxylarnine hydrochloride (6.95 g, 0.1 mmole) were dissolved in water (30 mL) and the anhydride of 2-carboxyphenylacetic acid (16.21 9, 0.1 mole) was added. The mixture was stirred rnanually. It became very thick and foamed excessively. More water was added and the mixture was heated on a steam bath. Within 2 minutes the mixture solidified. More water was added and the reaction mixture was fi'ltered. The crude product was recrystalli.zed from ethanol.
Melting Point: 200-201C.
Example 29 _Bromo-2~y~oxyquino ~ one The rnaterial prepared in Example 27 (1.09 9, 6.8 mmo'le) was dissolved in acetic acid (15 mL) and bromine (600 mg, 7.5 mmole) was added in 1 mL acetic 13~3376 acid, being careful to maintaln the temperature below 30. The starting material dissol~ed mid-way through the reaction and then 'later a new material precipitated. The mixture was diluted with water and the product col'lected by filtration. Recrystallization from nitromethane afforded f-luffy white needles (630 mg).
Melting Point: 197-199C.
NMR (DMS0-d6): 7.67-7.93 (m, 3H), 8.17 (s, lH), 8.3 (d, lH), 11.85 (s, lH).
IR (KBr): 1660, 1595,'1470, 765.
Mass Spectrum: 239, 241 (M+); 223, 196,' 194, 171, 169.
e 3Q
_Ni ~ 2~ d ox~quino'l-1(2H)-one The material prepared as in Example 27 (620 mg, 3.9 mmole) was dissol~ed in a mixture of acetic acid (2 mL), sulfuric acid (5 mL), and water (0.5 mL) and cooled to 0C. Sodium nitrite (800 mg, 11.6 rnrno'le) in water (2 mL) was added being careful to rnaintain the temperaturebe'low 10C. Qfter stirring f'or four hours the reaction mixture was diluted with water and a yellow precipitate ~ormed. The solid was filtered, dried, and recrystalli~ed form nitrometha.ne to afford 200 rng.
Melting Point: 163-165C dec.
NMR (~MS0-d6): 7.72 (t, lH), 7.97 (t, lH), 8.38 (t, lH), 8.62 (t, lH), 9.16 (s, lH).
Mass Spectrum: 206, 190, 176, 146, 129, 88.
_a~ _31 4-P~ -2-hvdrox~quinol-1(2H?-one 3-Pheny'_l _ndanone. ~rhe desired material was prepared according to the method of C.F. Koelsch, J. Qm.
Chem. Soc., 65, 59 (1943). Cinnamic acid (17 9) was dissol~ed in ben~ene (75 mL) and a'luminum chloride (50 g) was cautious'ly added. Qf'ter the initial ~igorous 131337 ~
reaction had subsided, the mix-ture was refluxed ~'or fiue hours. The reaction was quenched by pouring on ice, concentrated HCl was added and the mixture was extracted with benzene. The organic layer was washed with 2N NaOH
and distilled water, dried ouer magnesium sul~ate and euaporated ln uacuo. The residue was chromatographed on silica gel e'luting with 20% ether in pentane to afford 6.5 9 of white solid.
Melting Point: 74.5-75C.
IR (CDC].~): 3010, 1708(s), 1602, 1290, 1240.
Mass Spectrum: 208 (M+), 193, 178, 165, 152, 140, 130, 115.
4-Phen~1-2-hvdrox~uinol=~ -one. This step was patterned after the method of Chatterjee, Liebias ~nn. Chem.,52 (1981). To methanol (20 mL) under nitrogen at room temperature was added sodiurn metal (1.08 9, 47 mmole) in sma].l pieces. ~fter the sodiurn metal had been complete:ly consumed, the excess methanol was remo~ed ln uacuo. The resulting sodium methoxide was suspended in ether (50 mL) and cooled to 0C under . 20 nitrogen with uigorous stirring. ~n ether solution (15 mL) of butyl nitrite (1.67 mL, 14.3 rnmo'le) and 3-phenyl-1-indanone (prepared aboue, 2.08 g, 10 mmole) was added dropwise ouer 10 minutes. ~fter stirring for5 hours at 0C, the reacti.on flask was placed in a freezer (-10C) for 16 hours. l'he cold rnixture was then diluted with water (100 mL) and the aqueous layer was separated. The dark water layer was acidified (to litmus) with concentrated HCl. The precipitate which formed was collected and recrystallized from ethanol to afford 320 mg of tan crystals.
Melting Point: 202.5-204C
IR (KBr): 1605, 1495, 1345, 1325, 1170.
Mass ~pectrum: 237 (M+), 220, 192, 181, 165.
~313376 Example 32 4-Met~__2-hydroxY-quinol-~_H~
Using the method of Exarnple 27, except using 3-methyl-1-indanone, the desi.red material was obtained.
Me:lting Point: 207.5-209C.
NMR (DMS0-d6): 2.20 (s, 3H), 7.75-7.77 (m, 4H), 8.25 (m,lH).
IR (KBr): 1640, 1615, 1590, 1500, 1470, 1260.
Mass Spectrum: 175 (M+), 158, 147, 130, 115, 103.
Example 33 5-Meth~ =h~ quino1-2(1H~-one Using the method of Example 27, but using 4-methylindanone, the desired cornpound was obtained.
Melting Point: 180-182C.
Mass Spectrum: 175(M+), 158, 148, 130, 119, tO3.
E mple 34 ~
Using the method of Exarnple 27, but using 6-methoxyindanone, the desired compound was obtained.
Melting Point: 171~172C.
NMR (DMS0-d6): 3.88 (s, 3H), 6.59 (d, lH), 7.32-7.68 (m, 4H), 11.52 (s, lH).
IR (KBr): 1625, 1585, 1250, 1162, 861, 828, 613.
Mass Spectrum: l91(M+), 174, 146, 135, 117, 103.
_xample 35 ~ eh~ =--hydroxy~ui -2(1H)-one Using the method of Example 31, but using 2,3-diphenylindanone, the desired compound was obtained.
~31337 ~
NMR (DMS0-d6): 7,10-7.70 (m, 13H), 8.40 (d, lH), 11.14 (s, lH).
Mass Spectrurn: 313(M ), 296, 209, 193, 181, 165.
_amples _6 - 47 By using the method of Example 27 with the following starting materials, the indicated cornpounds can be prepared:
Ex. StartinQ_Materlal Product 36 2-Pentylindanone ~-Penty1-2-hydroxy-quinol-1(2H)-one 37 2-Methoxyindanone 3-Methoxy-2-hydroxy-quinol-1(2H)-one 38 3-Methoxyindanone 4-Methoxy-2-hydroxy--qwinol-1(2H)-one ~9 4-Methoxyindanone 5-Methoxy-2-hydroxy-quinol-1(2H)-one 4-Chloroindanone 5-~h'loro-2-hydroxy-quinol-1(2H)-one 41 5--Meihylindanone 6-Methyl-2-hydroxy-quinol-1(2H)-one 42 5-Methoxyindanone 6-Me-thoxy-1-hydroxy-quinol-1(2H)-one 43 5-Phenylindanone 6-Phenyl-2-hydroxy-quinol-1(2H)-one 44 5-8romoindanone 6-Bromo-2-hydroxy-' quinol-1(2H)-one 6-Methylindanone 7-Methyl-2-hydroxy-quinol-1(2H)-one 46 6-Phenylindanone 7-Phenyl-2-hydroxy-quinol-1(2H)-one 47 6-Bromoindanone 7-Bromo-2-hydroxy-quinol-lt2H)-one LipoxyQenase IC50 Deterrnination The compounds of this in~enti.on are potent inhibitors of 5-, 12-, and 15-lipoxygenases. ~n assay to determine 5-lipoxygenase acti~ity was performed in incubations containing ~arious concentrations of th test compound and the 20,000 g supernatant from 7.5 mi'l:Lion hornogenized RBL-l ce'lls. Reactions were initiated by addition of radiolabeled arachidonic acid ~3~3376 and terminated by acidification and ether extraction.Reaction products were separated from noncon~erted substrate by thin layer chromatography and measured by liquid scinti].lation spectroscopy.
Inhibition of 5-lipoxygenase acti~i-ty was calculated as the 50% intercept from linear regression analysis of percentage inhibition ~ersus :log concentration plots.
Results for compounds cf the foregoing exarnples are indicated in 'rable 1, be'low.
T~BLE 1 _ form la Substituent IC50(uM) 1 I -none-~ 5.3 2 I Rl=carbomethoxy 24 3 I R1=bromo 4.2 4 I R2=methyl 1.4 I R2,chloro, 1.6 R4.methoxy 6 I R3=nitro 3.7 7 I R3=nitro, R4=methyl 2.0 8 I R4=chloro 0.87 9 I R4=methyl 1.1 I R4--methoxy 1.5 11 I R4=nitro 14 12 I R4=phenyl 0.34 13 I R5=rnethyl 0.98 14 I R3,R4,benzo 0.84 15 . I/II Rl,R2=benzo 2.5 27 II -none- 6.0 28 II R1=hyclroxyl 54% @ lOOuM
29 lI R2=bromo 2.6 II R2=nitro 32% @ 30uM
31 II R2=pheny'l 0.45 32 l'I R2=rnethyl . 3.9 33 II R3=methy'l 2.4 34 II R5=methoxy 2.5 II R1,R2=phenyl 1.5 Inhibitory activities of the compounds of this in~ention against l2- and 15-lipoxygenase can be determined in the foregoing assay in which 12-lipoxygenase obtained from hurnan platelets, or 13~337 ~
l5-lipoxygenase obtained trom soybean, is substituted for the S-lipoxygenase containing cell supernatant fraction. Results of these tests for ~arious of the foregoing compounds are indicated in Table 2 Percent Inhibition at Indicated _ncentration Exam~ y~a_nase 15-li~_x~ e 100uM lOuM 100uM lOuM
2 94 66 1~ 5 8 97 95 lO0 95 ~7 90 94 62 16 98 93 g3 40 34 98 90 ~5 20 The foregoing is merely illustrati~e of the invention and is not intended to ].irni.t the in~ention to the disclosed compounds. ~ariations and change which are obvious to one skilled in the art are intended to be within the scope and nature of the in~ention which are defined in the appended claims.
Technical~Field This inuention relates to organic compounds which inhibit lipoxygenase enzymes. It also relates to methods of making such compounds, and to methods of inhibiting lipo~ygenase enzymes in human and animal hosts in need of such treatment.
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase conuerts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LTs).
Similarly 12- and 15-lipoxygenase, conuert arachidonic acid to 12- and 15-HPETE respectiuely. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-~P~TE
, is the precursor of the class of biological agents known as the lipoxins.
~ uariety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they haue been implicated as mediators in ~arious disease states. For example, the LTs C4 and D4 are potent constrictors of human airways ~n uitr_ and aerosol administration of these substances to non-asthmatic uolunteers induces broncho constriction. LTB4 and S-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also haue been found in the synouial fluid of rheumatoid arthritic patients. The biological actiuity of the LTs has been reuiewed by Lewis and ~ustin (J. Clinical Inuest. ~3, 889, 1984~ and by Sirois (~d~. Lipid Res. 21, r/8, 1985).
Bl The product 12-HElE has been found in high le~els in epidermal tissue of patients with psoriasis.
The lipoxins ha~e recently been shown to stimulate elastase and superoxide ion release from neutrophils.
Thus, lipoxygenase enzymes play an important role in the biosynthesis of mecdiators of asthma, allergy, arthritis, psoriasis, and in-flammation.
Blocking these enzyrnes interrupts the biochemical pathways in~ol~ed in these disease states.
Background ~rt Relati~ely few compownds are known from the prior ar~ which are inhibitors of the lipoxygenase enzymes. Qmonq the lipoxygenase inhibitors known to the art are: ~-861, a 5-lipoxygenase inhibitor, disclosed in U.S. Patent 4,393,075, issued July 12, 1983 to Terao et al.; pyrazolo pyridines, which are 5-lipoxygenase inhibitors, disclosed in European Patent ~pplication of Irikura et al., S.N. 121,806, published October 17, 1984; arachidonyl hydroxamic acid, a S-lipoxygenase inhibitor, disclosed in E. J. Corey et al., J. ~m. Chem.
Soc., 106, 1503 (1984) ancl European Patent ~pplicati.on of P.H. Nelson, S.N. 104,468, published ~pril 4, 1984;
BW755C, inhibitor of 5- and 12-lipoxygenases, disclosed in Radmark et al., FEBS Lett., 110, 213 (1980);
nordihydroguariaretic acid; an inhibitor of 5- and 15-lipoxygenases, disclosed in Morris et al., Prostaqlandins, 19, (1980); RE~-5901, a S-lipoxygenase inhibitor, disclosed in Coutts, Meeting ~bstract 70, Prostaglandins and _eukotrienes '84, quinoline N-oxides, 5-lipoxygenase inhibitors disclosed in Ewropean patent application of Hashizumo et al., S.N. 128,374, published December 19, 1984 and benoxaprofen, disclosecl in J.
Walker, Pharm. Pharmacol., 31, 778 (1979). It would b~
useful to ha~e compounds which are more po-tent inhibitors of these enzymes.
13~33~
In addition a nulnber of compounds identified as ha~ing sorne lipoxygenase inhibitory acti~ity are structurally related to arachidonic acid. Such compounds are highly swsceptible to oxidation in ~itro and to breakdown by con~entional pathways of lipid rnetabolisrn ln Vl~O. l-hus as well as hauing the desired potency it would be desirable to ha~e agents which are relati~ely simple in structure, and relatiuely resistant to oxidation and metabolism.
It is an object of the present in~ention to pro~ide cornpounds which are highly potent inhibitors of lipoxygenase enzymes.
It is another object of this in~ention to pro~ide cornpounds ha~ing structures which are simpler and more stab].e than prior art compounds ha~ing lipid-like structures.
It is yet another object of this in~ention to pro~ide cornpounds which inhibit lipoxygenase activi-ty in ~J i IJ o .
These and other objects of this invention will be e~ident from the following disclosure.
Disclosure oF the In~ention ____.__ ___ Thc? present i.n~ention pro~ides for compounds and methods of using cornpounds of the formulae I and II
in inhi.biting lipoxygenase enzyme acti~ity:
~M R
R5 ~ N ~ O R5 ~ ,,OM
R4~R1 ~
where R1 through R5 are 1ndependently selected from hydrogen, Cl-C12 alkyl, alkoxy, carboalkoxy, aryl, nitro, hydroxy, halogen; or where Rl-R2, R3-R4, R4-R5 forrn an arornatic Fused ring; and where M is a pharmaceutically acceptable cation, Cl-C12 alkyl, acyl, or trialkyl silyl.
_4_ ~313376 rhe term alkyl ls wsed herein to mean straight and branched chai.n radicals, including, but not limited to methyl, ethyl, n-propyl, isopropy:l, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The term alkoxy is used herein to mean straight and branched chained oxygen ether radica].s, including, but not limited to methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
The term carboalkoxy is used herein to mean straight or branched chain ester radicals appended at the carbonyl carbon, including, but not limited to carbomethoxy, carboethoxy, carboisopropoxy, carbo-tert-butoxy and the like.
The term acyl is used herein to rnean straight or branched chain carbonyl radicals, including but not limited to, -formyl, acet~l, propionyl, butyryl, isobutyryl and the like.
The term aryl is used herein to mean substituted and unsubstituted aromatic radicals, including, but not lirnited to phenyl, l-napthyl, 2-napthyl and the like.
The term aromatic fused ring is used herein to mean substituted and unsubstituted benzene rings fused to the carbon skeleton of I or II.
The term "pharrnaceutical'ly acceptab'le cation"
is used herein to mean hydrogen and the nontoxic cations based on the alka'li and a'lka:line earth metals, such as sodium, lithium, potassium, magnesium, and the like, as well as those based on nontoxic ammonium, quaternary ammoniurn, and amine cations, including, but not limited to, ammonium, tetramethy:lammonium, tetraethylammonium, methyl amine, dimethyl amine, trirnethyl amine, triethyl amine, ethyl amine, and the like.
_5_ ' 1313376 Method _ T_eatment This in~ention also pro~ides a rnethod of treatrnent ot' inhibiting 5-, 12- and/or 15-lipoxygenase acti~ity in a human or lower animal host.in need of such treatment which rnethod comprises administration to the human or lower anirna'l host an amount of a compound of this in~ention eff'ecti~e to inhibit lipoxygenase acti~ity in the host. The compounds of the present in~ention may be adrninistered oral'ly, parenterally or topically in dosage unit formwlations containing con~entional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
The term parenteral as used herein includes subcutar,eous, intra~enous, intramuscular, intrathecal, intraarticular, epidura'l and intraarterial injection or infusion techniqwes, without lirnitation. The term "topically" encornpasses adrninistration rectally and by inhalation spray, as well as by the more common routes of the skin and the mucous membranes of the mouth and nose.
Total daily dose of the compounds of this inuention administered to a host in single or di~ided doses may be in amounts, for example, of from O.OOl to 100 rng/kg body weight dai'ly and more usual~y 0.01 to 10 mg/kg/day. Dosage.wnit cornpositions may contain such amounts or such subrnultiples thereof as may be used to make up the daily dose. It wil]. be understood, howe~er, that the specific dose le~el for any particular patient will depend upon a ~ariety of factors including the acti~ity of the specific compound employed, the age, body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
-6- 1~13376 F rmulation of Pharmaceutical Co~ _it.ions T'his in~enti.on also pro~ides for compositions in unit dosage t'orm for the inhibition of 5-, 12-, or 15-lipoxygenase acti~ity in a human or lower animal host in need of such treatment, comprising a compound of this in~ention and one or more nontoxic pharrrlaceuti.cally acceptable carriers, adju~ants or ~ehic:les. 'rhe amount of active ingredient that may be combined with such materials to produce a sing'le dosage-form will vary depencding upon uarious factors, as indicated above.
~ ~ariety of materials can be used as carriers, adjuvants and ~ehicles in the compositions of this in~ention, as a~ailable in the pharmaceutical arts.
Injectable preparations, such as sterile injectable aqueous or oleaginous solutions, suspensions or emulsions, may be formulated according to known art, using suitable dispersing or wetting agents and suspending agents, as needed. The steri.le injectable preparation may employ a nontoxic parenterally acceptable diluent or sol~ent as, for example, sterile, nonpyrogenic water or 1,3-butanediol. ~irnong the other acceptable ~ehicles and sol~ents that may be employed are 5% dextrose injection, Ringer's injection and isotonic sodium chloride injection (as described in the USP/NF). In addition, sterile, fixed oils are conuentiona].].y emp].oyed as sol~ents or suspending media. For this purpose any bland fixed oil may be used, inclucling synthetic rnono-, di- or triglycerides.
Fatty acids such as o'leic acid can also be used in the preparation of injectable compositions.
Suppositories for rectal adminis-tration of the compounds of this in~ention can be prepared by mixing the drug with suitable nonirritating excipients such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at body temperature and which therefore melt in the recturn and release the drug.
-7~ ~3 1~ 37 6 ~olid dosage forms for oral adrninistration include capsules, tablets, pills, troches, lozenges, powders and granu:Les. Ln such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. ~uch dosage forms may also comprise, as is normal practice, pharmaceutical adjuvant substances, e.g., stearate lubricating agents. In the case of capsules, tablets and pills, the dosage forms rnay also comprise bufFering agents. Solid oral preparations can also be prepared with enteric or other coatings which modulate release of the acti~e ingredients.
Liquid dosaye forms for oral administration inclu~e pharmaceutically acceptable emulsions, solutions, suspensior1s, syrups and elixirs containing inert nontoxic diluen-ts commonly used in the art, such as water and alcohol. Such cornpositions may also comprise adju~ants, such as we-tting agents, emulsifying suspending, sweetening; fla~oring and perfuming agents.
~y~_S15 O - .he Compounds Cornpounds of this in~enti.on ha~iny formula I
can be prepared according to the reaction sequence Q
below. Qlthough the sequence illustrates the compound where R is hydrogen, it will be seen from the examples that other compounds of this invention can be prepared in the same manner using the appropriate starting materials.
~ ~H3COOOH ~ ~ 2 I OAC OH
~ ~ H~l ~ ~
-8- ~ 3~3~5 Quinoline (1) is treated with peracetic acid to af-ford quinoline N-oxide (2) which is treated with l~ad tetraacetate to yield l-acetoxyquinol 2~1H)-one (3), The N-hydroxyqwinolone (4) is obtained by heating (3) with 2N HCl.
Compounds of this in~entioll ha~ing formula II
can be prepared according to reac-tion sequencc B below.
~lthough sequence B illustrates the compound where R is hydrogen, it will be seen from the examples that other compounds of this in~ention can be prepared in the salne manner using the appropriate starting materials.
OTBDMS
TBDMSCI~ ~ 2 (CH3)2S ~ OHHo NaOAc~' B 8 OH~ 9 Indanone (5) is con~erted to its corresponding silyl eno'l ether (6) with trimethylsilyl chloride or t-butyldimethylsi.lyl chloride and -triethylarnine or sodium bis-trimethylsilylamide and t-buty'ldimethy'lsilyl chloricle. 070nolysis of (6) followed by a reducti~e work-up with dimethylsulfide yields the a'ldehyde acid (7). Reaction with hydroxylamine affords oxime (8) and then heating yields the 2-hydroxyquinol-1(2H)-one (9).
In addition to the method described above, compounds of this in~ention ha~ing formula II where R
~313376 g and R2 are other than hydrogen can be prepared according to reaction scheme C below.
n o n BuONO ~ ~ N-OH
R NaOCH3 ~ R
Indanone (lO) is treated with n-butylnitrite to give 2-hydroxyquinol-1(2H)--one directly.
rhe following examples further illustrate the synthesis and use of compounds of this invention.
_xample l l-hvdr ~yg _nol-2-(1H ? -one Quinollne N-oxide. Peracetic acid (7.5 mL, 39 mmole, 40%) and quinoline (5 9, 39 mmole) were stirred for 2 hours. Much of the acetic acid was removed from the reaction mi.xture in u_cuo. The resulting residue was dissolved in methylene chloride (50 rnL) and washed twice with saturated soclium bicarbonate solution. Qfter drying ouer MgSO~ the soluent was euaporated and the residue was triturated with ether. The resulting tan solid was col'lected by filtration. This material was carried on without further characterization.
~=~Y~ y~u ~ ) one. The desired material was prepared according to the method of Ochiai and Ohta, Chern ~bstr., 59, 2766, (1963). The crude material prepared as described aboue (approximately 5.5 9) was dissolued in benzene (lOO mL) and CaCO3 (0.50 9, 5.0 mmole) and 'lead tetraacetate (20.0 9, 45.1 mmole) were added. The mixture was refluxed for two hours.
The lead by-products which precipitated were filtered off and rinsed with methylene chloride. The soluent was euaporated in uacu to giue a very dark oil.
Hydrochloric acid (2N, 25 mL) was added and refluxed for 30 minutes. ~ brown solid formed which was isolated by filtrati.on and recrystallized from benzene.
Melting Point: 188C.
Example 2 3 a _ometho~y~ droxyqu _ol-~lH)-one ~ c rbomethoxy_3~2-n _ro~he~yl~-p~E__oate. l'he desired material was prepared according to the method described in J. Chem. Soc., 3462 (1960).
Dimethyl rna.Lonate (5.28 g, 40 mrnole), acetic anhydride (15.08 mL, 160 mL), sodium bicarbonate (5.04 g, 40 mmole), and 2-nitrobenzaldehyde were heated at 100C for 2 hrs. ~fter cooling, the rnixture was diluted with water, extracted into ether and washed with saturated sodium bicarbonate. The solvent was rerno~ed ln uacuo and the residue chromatographed, eluting with 45% ether - in pentane. ~ yellow oi]. (2.7 g) was obtained. It crystallized on standing.
3-Ca bom _h x~-1-hvdrox\/quinol-?(lH)-one. l'he desired material was prepared according to the method found in J._Chem. Soc. C, Y13, (1969). To a water solution (20 mL) of sodium borohydride (0.75 g, 20 mmole) and 10% palladium on charcoal (O.OY5 9) was added a me-thanol solution (20 mL) of the diester prepared as abo~e (2.7 g, 10 mmole). The rnixture was stirred at room temperature f'or thirty minutes and then f'iltered.
The filtrate was acidified with concentrated HCl and the solid which t'ormed was recrystallized ~'rom water to afford 700 mg of fine needles.
~elting Point: 170-171C.
IR (KBr): 3450, 1740, 1708, 1625, 1580, 1304, 792, 755.
Mass Spectrum: 219 (M+), 203, 187, 172, 143, 115.
1~3376 xample 3 3-Bromo-l-hyclrox~/quinol-2 ~ 2 __ Using the method of Example 1, but using 3-brornoquinoline, the desired compound was obtained.
Melting Point: 185-.L86~.
IR (KBr): 3070(br), 1620(s), 1580(s).
Mass Spectrum: 239, 241 (M+); 225, 223, 196, 194.
~m~L
~=e~ Ll~droxvquinol=2(lH~
Using the method of Example 1, but using 4-methylquinoline the desired cornpound was obtained.
Melting point: 187C.
IR (KBr): 1640, 1612, 1590, 970, 780, Mass Spectrwrn: 161 (M+), 134, 116, 105.
Exame~ 5 4-Chloro-6-rnetho~ L_oxy~L__o~ -one Using the method of Example 1, but using 4-chloro-6-methoxyqwinoli.ne, the desired compound was obtained.
Melting Point: 210-215C (dec).
NMR (DMS0-d6): 3.92 (s, 3H), 7.03 (s, lH), 7.29-7.41 (m, 3H).
Mass Spectrurn: 225, 227(M ), 210, 208, 201, 180.
le 6 ~-Nitro-l-hydroxyquinol-2(1H)-one -Using the method of Exarnple 1, but using 5-nitroquinoline, the desired compound was obtairled.
Melting Point: 205C (sublime).
NMR (DMS0-d6): 6.96 (d, lH), 7.84 (t, lH), 7.g7 (d, lH), 8.03 (d, lH), 8.23 (d, lH), 11.83 ~s, lH).
Mass Spectrum: 206 ~M ), 190, 174, 160, 130, .~5 115 1~133~
Example 7 _-Methy1-5--nitro-1-hvdrox~quinol-?(lH)-one Using the method of ~xample 1, but using 6-methyl-5-nïtroquinoline, the desired compound was obtained.
Melting Point: 230C (dec).
NMR (DM~0-d6): 2.35 (s, 3H), 6.87 (d, lH) 7.65-7.88 (m, 3H), 11.76 (s, lH).
Mass ~pectrum: 220 (M ), 203, 186, 175, 157, 145, 128, 115.
~e~
6-Chlor~ roxyquinol-2(1H)-one Using the method of Example 1, but using 6-chloroquinoline the desired compound was obtained Melting Point: 175-177C.
IR (KBr): 1640, 1625, 1420, 820, 812.
Mass Spectrum: 195, 197 (M~); 178, 150, 138, 123, 114 Exarnple 9 6-Meth~ drox~qui~ IH)-one Using the method of Example 1, but using 6-methylquinoline, the desired compound was obtained Melting Point: 201-202C.
:[R (KBr): 3050(br); 1625(br,s); 1580(br,s).
Mass Spectrum: 175 (M~), 158, 146, 130, 118, 103.
Exam~le 10 6-Me~h~ ~1r~quinol-?-~lH)-one Using the method of Example 1, but using 6-methoxyquinoline, the desired compound was obtained.
Melting point: 193-194C.
13~3376 NMR ~CDC13): 3.80 (s, 3H), 6,72 (d, lH, J=9Hz), 7.30 (m, 2H), 7.62 (d, lH, J=9Hz), 7.85 (d, 1H, J=9Hz).
IR (KBr): 1630, 1573, 1250, 1163, 830.
Mass Spectrum: 191(M+), 174, 146, 132, 120, 103.
E am~le 11 6-Nitro~l_h~Lr x~quinol _ ~H)-one Using the method of Example 1, but using 6-nitroquinoline, the desired compound was obtained.
Melting Point: 184-185C (dec).
IR (KBr): 1665, 1620, 1520, 1345, 835.
Mass Spectrum: 206 (M+), l90, 176, 160, 144, 132, 116.
Example 12 6-Phen~l-l-hydroxy~u o ~ -one Using the method of Example l, but using 6-phenylquino:Line, the desired compound was obtained.
Melting Point: 219-220C.
IR (K~r): 1670, 1590, 1571, 1425, 818, 759.
Mass Spectrum: 23Y (M ), 220, 192, 165, 152.
~ le 13 7 Meth~ LU_ ol-_~lH~ e Using the method of Example 1, but using 7-methylquinoline the desired compound was obtained.
Melting Point: 170-172 NMR (DMS0-d6): 2.45 (s, 3H), 6.63 (d, lH), 7.10 (d, lH), 7.5 (s, lH), 7.65 (d, lH), 7.86 (d, lH), 11.30 (d, lH).
IR (KBr): 1640, 1500, 1407, 1163, 855.
Mass Spectrum: 175 (M~), 158, 146, 130, 118, 103.
~31337G
Eæl_ 14 ~ Benzo-1-~ dr~ Lj~5LH)-one Using the method of ~xamp'le 1, but using 5,6-benzoquinoline, the desired compound was obtained.
Me'lting Point: 240C dec, NMR (~MS0--d6): 6.87 (d, lH), 7.55-8.85 Irn, 7H).
~ass Spectrum: 211 (M ), l9S, 182, 166, 154, 139, 127.
~me~
3,4-8enzo-1-h~Lrox~quinol-2~
Using the method of Example 1, but using 3,4-benzoquinoline the desired cornpound was obtained Melting Point: 238-240C dec.
IR (KBr): 3050(br); 1625(s); 1604(s); 1590(s).
Mass Spectrurn: 211 (M+), 195, 166, 140.
ExarnPles l~i - 2 By using the method of Example 1 with the following starting materials, the indicat'ed compounds can be prepared:
Ex. St r_ n~Q~_ate ial P_oduct 16 3-Isopropylquino:Line 3-1sopropyl-1-hydroxy-quinol-2(1H)-one 17 3-Phenylquinoline 3-Phenyl-l-hydroxy-quinol-2(1H)-one 18 3-Chloroquinoline 3-Chloro-l-hydroxy-quinol-2(1H)-one 19 4-Ethylquinoline 4-Ethyl-l-hydroxy-quinol-2(1H)-one 4-Nitroquinoline 4-Nitro-l-hydroxy-quinol-2(1H)-one 21 5-Methylquinoline 5-Methyl-l-hydroxy-quinol-2(1H)-one 22 5-Methoxyquinoline 5-Methoxy-l-hydroxy-quinol-2(1H)-one 23 6-Carbomethoxyquinoline 6-Carbomethoxy-l-hydroxyquinol-2(lH)--one 24 6,7--Benzoquino'line 6,7-Benzo-l-hydroxy-quinol-2(1H)-one 7-Methoxyquinoline 7-Methoxy-l-hydroxy-quinol-2(1H)-one 26 l-Phenylquino:line 7-Phenyl-l-hydroxy-quinol-2~1H)-one Example 27 2-h!~r x~ol~-one l-Trimethvlsilox~indene. Trimethylsilyl chloride (5.7 9, 52.3 mrnole), triethylarnine (11.71 9, 116 mmole), and l-indanone (6.22 9, 47.1 mmole) were dissol~Jed in dimethyl forrnamide (25 mL) and refluxed for 17. hours. ~fter cooling, the mixture was diluted wi-th pentane (50 rnL) and washed four tirnes with saturated sodium bicarbonate. ~fter backwashing the aqueous phase with pentane the organic layers were combined, washecl with cold 2N HCl and cold saturated sodium bicarbonate, then dried ouer MgS04. The sol-lent was e~aporated and the residue distil'led (bp 123-125C).
NMR (CDC13): 0.35 (s, 9H); 3.3 (d, 2H, J=2 Hz); 5.45 (t, lH, J'=2 Hz); 7.2-7.6 (m, 4H).
(~-Ca b_X!/P_ny~taldeh~. Ozone was bubbled through a methanol solution ~25 mL) of the silyl enol ether prepared above (1 9, 4. ~ rnrnole) at -78 .
~fter fi~le minutes the reaction turned blue indicating the end of the reaction. ~f'ter purging with nitrogen, the reaction was quench~d with dimethylsulfide (1 g, 16,1 mmole) and stirred for two hours at 0 . The soluent was e~Japorated and the residue chromatographed (eluting with ether/hexane) to aff'ord 0.5 g of a white s oli d .
NMR (CDC13): 3.2 (d, 2H, J=4 Hz), 5.9 (t, lH, J=4 Hz), 7.0-8.2 (m, 4H) .
Mass Spectrurn: 165, 164 (M+), 147, 136, 118, 90 .
~boxl/phenvl~acetaldeh~e o me. This step was patterned after the method of Robinson, J. ~m. Chem.
Soc., 80, 3443 (1958). The material prepared abo~Je (350 mg, 2.1 mrno'le) was suspended in 5 mL water and heated to clissol~e . Hydroxy'lamine (213 mg, 3.1 mmole) and sodium acetate (254 rng, 3.l mmole) were added and the rnixture was heated for 15 minutes. ~fter cooling a solid precipitated which was recrystallized from nitromethane to afford 145 mg of a white solid. This was carried on without characterization.
_~L roxy=gLu nol-1(2H~_one. The material (140 mg, 0.8 mmole) prepared above was dissolved in xylene and heated to 130 for three hours. Upon cooling a yellow solid precipitated which was recrystallized from nitromethane to afford a tan solid (70 mg).
Melting Point: 187-188C.
NMR (DMS0-d6): 6.62 (d, lH), 7.47-7.80 (m, 4H), 8.25 (d, 1H).
IR (KBr): 3100(br), 1640(s), 1612(s), 1585(s), 780.
Mass Spectrum: 161 (M~), 134, 116, 105, 89.1 Ex_~___28 2,3-Di~L_r~ ulnol--_(2H2-one.
Sodium carbonate (5.3 g, 0.05 rno'le) and hydroxylarnine hydrochloride (6.95 g, 0.1 mmole) were dissolved in water (30 mL) and the anhydride of 2-carboxyphenylacetic acid (16.21 9, 0.1 mole) was added. The mixture was stirred rnanually. It became very thick and foamed excessively. More water was added and the mixture was heated on a steam bath. Within 2 minutes the mixture solidified. More water was added and the reaction mixture was fi'ltered. The crude product was recrystalli.zed from ethanol.
Melting Point: 200-201C.
Example 29 _Bromo-2~y~oxyquino ~ one The rnaterial prepared in Example 27 (1.09 9, 6.8 mmo'le) was dissolved in acetic acid (15 mL) and bromine (600 mg, 7.5 mmole) was added in 1 mL acetic 13~3376 acid, being careful to maintaln the temperature below 30. The starting material dissol~ed mid-way through the reaction and then 'later a new material precipitated. The mixture was diluted with water and the product col'lected by filtration. Recrystallization from nitromethane afforded f-luffy white needles (630 mg).
Melting Point: 197-199C.
NMR (DMS0-d6): 7.67-7.93 (m, 3H), 8.17 (s, lH), 8.3 (d, lH), 11.85 (s, lH).
IR (KBr): 1660, 1595,'1470, 765.
Mass Spectrum: 239, 241 (M+); 223, 196,' 194, 171, 169.
e 3Q
_Ni ~ 2~ d ox~quino'l-1(2H)-one The material prepared as in Example 27 (620 mg, 3.9 mmole) was dissol~ed in a mixture of acetic acid (2 mL), sulfuric acid (5 mL), and water (0.5 mL) and cooled to 0C. Sodium nitrite (800 mg, 11.6 rnrno'le) in water (2 mL) was added being careful to rnaintain the temperaturebe'low 10C. Qfter stirring f'or four hours the reaction mixture was diluted with water and a yellow precipitate ~ormed. The solid was filtered, dried, and recrystalli~ed form nitrometha.ne to afford 200 rng.
Melting Point: 163-165C dec.
NMR (~MS0-d6): 7.72 (t, lH), 7.97 (t, lH), 8.38 (t, lH), 8.62 (t, lH), 9.16 (s, lH).
Mass Spectrum: 206, 190, 176, 146, 129, 88.
_a~ _31 4-P~ -2-hvdrox~quinol-1(2H?-one 3-Pheny'_l _ndanone. ~rhe desired material was prepared according to the method of C.F. Koelsch, J. Qm.
Chem. Soc., 65, 59 (1943). Cinnamic acid (17 9) was dissol~ed in ben~ene (75 mL) and a'luminum chloride (50 g) was cautious'ly added. Qf'ter the initial ~igorous 131337 ~
reaction had subsided, the mix-ture was refluxed ~'or fiue hours. The reaction was quenched by pouring on ice, concentrated HCl was added and the mixture was extracted with benzene. The organic layer was washed with 2N NaOH
and distilled water, dried ouer magnesium sul~ate and euaporated ln uacuo. The residue was chromatographed on silica gel e'luting with 20% ether in pentane to afford 6.5 9 of white solid.
Melting Point: 74.5-75C.
IR (CDC].~): 3010, 1708(s), 1602, 1290, 1240.
Mass Spectrum: 208 (M+), 193, 178, 165, 152, 140, 130, 115.
4-Phen~1-2-hvdrox~uinol=~ -one. This step was patterned after the method of Chatterjee, Liebias ~nn. Chem.,52 (1981). To methanol (20 mL) under nitrogen at room temperature was added sodiurn metal (1.08 9, 47 mmole) in sma].l pieces. ~fter the sodiurn metal had been complete:ly consumed, the excess methanol was remo~ed ln uacuo. The resulting sodium methoxide was suspended in ether (50 mL) and cooled to 0C under . 20 nitrogen with uigorous stirring. ~n ether solution (15 mL) of butyl nitrite (1.67 mL, 14.3 rnmo'le) and 3-phenyl-1-indanone (prepared aboue, 2.08 g, 10 mmole) was added dropwise ouer 10 minutes. ~fter stirring for5 hours at 0C, the reacti.on flask was placed in a freezer (-10C) for 16 hours. l'he cold rnixture was then diluted with water (100 mL) and the aqueous layer was separated. The dark water layer was acidified (to litmus) with concentrated HCl. The precipitate which formed was collected and recrystallized from ethanol to afford 320 mg of tan crystals.
Melting Point: 202.5-204C
IR (KBr): 1605, 1495, 1345, 1325, 1170.
Mass ~pectrum: 237 (M+), 220, 192, 181, 165.
~313376 Example 32 4-Met~__2-hydroxY-quinol-~_H~
Using the method of Exarnple 27, except using 3-methyl-1-indanone, the desi.red material was obtained.
Me:lting Point: 207.5-209C.
NMR (DMS0-d6): 2.20 (s, 3H), 7.75-7.77 (m, 4H), 8.25 (m,lH).
IR (KBr): 1640, 1615, 1590, 1500, 1470, 1260.
Mass Spectrum: 175 (M+), 158, 147, 130, 115, 103.
Example 33 5-Meth~ =h~ quino1-2(1H~-one Using the method of Example 27, but using 4-methylindanone, the desired cornpound was obtained.
Melting Point: 180-182C.
Mass Spectrum: 175(M+), 158, 148, 130, 119, tO3.
E mple 34 ~
Using the method of Exarnple 27, but using 6-methoxyindanone, the desired compound was obtained.
Melting Point: 171~172C.
NMR (DMS0-d6): 3.88 (s, 3H), 6.59 (d, lH), 7.32-7.68 (m, 4H), 11.52 (s, lH).
IR (KBr): 1625, 1585, 1250, 1162, 861, 828, 613.
Mass Spectrum: l91(M+), 174, 146, 135, 117, 103.
_xample 35 ~ eh~ =--hydroxy~ui -2(1H)-one Using the method of Example 31, but using 2,3-diphenylindanone, the desired compound was obtained.
~31337 ~
NMR (DMS0-d6): 7,10-7.70 (m, 13H), 8.40 (d, lH), 11.14 (s, lH).
Mass Spectrurn: 313(M ), 296, 209, 193, 181, 165.
_amples _6 - 47 By using the method of Example 27 with the following starting materials, the indicated cornpounds can be prepared:
Ex. StartinQ_Materlal Product 36 2-Pentylindanone ~-Penty1-2-hydroxy-quinol-1(2H)-one 37 2-Methoxyindanone 3-Methoxy-2-hydroxy-quinol-1(2H)-one 38 3-Methoxyindanone 4-Methoxy-2-hydroxy--qwinol-1(2H)-one ~9 4-Methoxyindanone 5-Methoxy-2-hydroxy-quinol-1(2H)-one 4-Chloroindanone 5-~h'loro-2-hydroxy-quinol-1(2H)-one 41 5--Meihylindanone 6-Methyl-2-hydroxy-quinol-1(2H)-one 42 5-Methoxyindanone 6-Me-thoxy-1-hydroxy-quinol-1(2H)-one 43 5-Phenylindanone 6-Phenyl-2-hydroxy-quinol-1(2H)-one 44 5-8romoindanone 6-Bromo-2-hydroxy-' quinol-1(2H)-one 6-Methylindanone 7-Methyl-2-hydroxy-quinol-1(2H)-one 46 6-Phenylindanone 7-Phenyl-2-hydroxy-quinol-1(2H)-one 47 6-Bromoindanone 7-Bromo-2-hydroxy-quinol-lt2H)-one LipoxyQenase IC50 Deterrnination The compounds of this in~enti.on are potent inhibitors of 5-, 12-, and 15-lipoxygenases. ~n assay to determine 5-lipoxygenase acti~ity was performed in incubations containing ~arious concentrations of th test compound and the 20,000 g supernatant from 7.5 mi'l:Lion hornogenized RBL-l ce'lls. Reactions were initiated by addition of radiolabeled arachidonic acid ~3~3376 and terminated by acidification and ether extraction.Reaction products were separated from noncon~erted substrate by thin layer chromatography and measured by liquid scinti].lation spectroscopy.
Inhibition of 5-lipoxygenase acti~i-ty was calculated as the 50% intercept from linear regression analysis of percentage inhibition ~ersus :log concentration plots.
Results for compounds cf the foregoing exarnples are indicated in 'rable 1, be'low.
T~BLE 1 _ form la Substituent IC50(uM) 1 I -none-~ 5.3 2 I Rl=carbomethoxy 24 3 I R1=bromo 4.2 4 I R2=methyl 1.4 I R2,chloro, 1.6 R4.methoxy 6 I R3=nitro 3.7 7 I R3=nitro, R4=methyl 2.0 8 I R4=chloro 0.87 9 I R4=methyl 1.1 I R4--methoxy 1.5 11 I R4=nitro 14 12 I R4=phenyl 0.34 13 I R5=rnethyl 0.98 14 I R3,R4,benzo 0.84 15 . I/II Rl,R2=benzo 2.5 27 II -none- 6.0 28 II R1=hyclroxyl 54% @ lOOuM
29 lI R2=bromo 2.6 II R2=nitro 32% @ 30uM
31 II R2=pheny'l 0.45 32 l'I R2=rnethyl . 3.9 33 II R3=methy'l 2.4 34 II R5=methoxy 2.5 II R1,R2=phenyl 1.5 Inhibitory activities of the compounds of this in~ention against l2- and 15-lipoxygenase can be determined in the foregoing assay in which 12-lipoxygenase obtained from hurnan platelets, or 13~337 ~
l5-lipoxygenase obtained trom soybean, is substituted for the S-lipoxygenase containing cell supernatant fraction. Results of these tests for ~arious of the foregoing compounds are indicated in Table 2 Percent Inhibition at Indicated _ncentration Exam~ y~a_nase 15-li~_x~ e 100uM lOuM 100uM lOuM
2 94 66 1~ 5 8 97 95 lO0 95 ~7 90 94 62 16 98 93 g3 40 34 98 90 ~5 20 The foregoing is merely illustrati~e of the invention and is not intended to ].irni.t the in~ention to the disclosed compounds. ~ariations and change which are obvious to one skilled in the art are intended to be within the scope and nature of the in~ention which are defined in the appended claims.
Claims (25)
1. A compound of the formula where R1 is selected from chloro, fluoro, iodo, aryl selected from phenyl, 1-naphthyl or 2-naphthyl;
straight or branched C1-4 carboalkoxy, straight or branched C1-4 alkoxy or C5-C12 alkyl; and where R2-R5 independently are selected from hydrogen, C1 to C8 alkyl, alkoxy as defined above, aryl as defined above, halo, nitro, or carboalkoxy as defined above; or R1-R2, R3-R4 or R4-R5 independently form a benzene ring, provided that R2-R5 are not all hydrogen when R1 is carboalkoxy as defined above, and R3-R5 are not all hydrogen when R1-R2 is a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
straight or branched C1-4 carboalkoxy, straight or branched C1-4 alkoxy or C5-C12 alkyl; and where R2-R5 independently are selected from hydrogen, C1 to C8 alkyl, alkoxy as defined above, aryl as defined above, halo, nitro, or carboalkoxy as defined above; or R1-R2, R3-R4 or R4-R5 independently form a benzene ring, provided that R2-R5 are not all hydrogen when R1 is carboalkoxy as defined above, and R3-R5 are not all hydrogen when R1-R2 is a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
2. A compound of the formula where R1 is C1-4 alkyl, methoxy or ethoxy, and R2-R5 independently are selected from C2-C12 alkyl, straight or branched C1-4 alkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro, or straight or branched C1-4 carboalkoxy; or where independently R3-R4 or R4-R5 form a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
3. A compound of the formula where R1 is selected from C3-C12 alkyl, straight or branched C1-4 alkoxy, aryl selected from 1-naphthyl or 2-naphthyl, halo, nitro, hydroxy or straight or branched C1-4 carboalkoxy; R2-R4 independently are selected from hydrogen, C1-C8 alkyl, alkoxy as defined above, aryl selected from phenyl, 1-naphthyl or 2-naphthyl: halo, nitro, hydroxy or carboalkoxy as defined above; or where independently R2-R3 or R3-R4 form a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
4. A compound of the formula where R1 is bromo or nitro, R2 is selected from C1-C8 alkyl, straight or branched C1-4 alkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro or straight or branched C1-4 carboalkoxy and R3-R5 independently are selected from hydrogen, C1-C8 alkyl, alkoxy as defined above, aryl as defined above, halo, nitro, hydroxy, carboalkoxy as defined above; or where independently R3-R4 or R4-R5 form a benzene ring: M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have 1 to 6 carbon atoms.
5. A compound of the formula where R1-R4 independently are selected from hydrogen, C1-C8 alkyl, straight or branched C1-4 alkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro, hydroxy or straight or branched C14 carboalkoxy, provided that:
R1-R4 are not all hydrogen, R1 is not hydroxy or chloro when R2-R4 are hydrogen, neither R2 nor R3 are nitro when the remainder of R1-R4 are hydrogen, R3 is not bromo when the remainder of R1-R4 are hydrogen, and R3 and R4 are not simultaneously methyl when R1 and R2 are hydrogen;
or where independently R2-R3 or R3-R4 form a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C14 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
R1-R4 are not all hydrogen, R1 is not hydroxy or chloro when R2-R4 are hydrogen, neither R2 nor R3 are nitro when the remainder of R1-R4 are hydrogen, R3 is not bromo when the remainder of R1-R4 are hydrogen, and R3 and R4 are not simultaneously methyl when R1 and R2 are hydrogen;
or where independently R2-R3 or R3-R4 form a benzene ring; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C14 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
6. A compound of the formula wherein R1 is selected from C5 to C8 alkyl, straight or branched C1-4 alkoxy, straight or branched C1-4 carboalkoxy, aryl selected from 1-naphthyl or 2-naphthyl, halo, nitro, hydroxy; R2-R5 independently are selected from hydrogen, lower alkyl, alkoxy as defined above, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro, or carboalkoxy as defined above or R1-R2, R3-R4 or R4-R5 independently form a benzene ring, provided that R3-R5 are not all hydrogen when R1-R2 is a benzene; M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
7. A compound of the formula where R1 is selected from hydrogen, C2 to C8 alkyl, straight or branched C1-4 alkoxy, straight or branched C1-4 carboalkoxy, fluoro, chloro, iodo, nitro, hydroxy, or aryl selected from 1-naphthyl or 2-naphthyl; R2-R4 independently are selected from hydrogen, C1-C8 alkyl, alkoxy as defined above, carboalkoxy as defined above, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro, or R2-R3 or R3-R4 independently form a benzene ring, provided that R1-R4 independently form a benzene ring, provided that R1-R4 are not all hydrogen and R3-R4 are not simultaneously methoxy when R1 and R2 are hydrogen: M is a pharmaceutically acceptable cation, C1-C12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from 1 to 6 carbon atoms.
8. A compound of the formula where R1 is selected from C1 to C4 alkyl and R2-R5 independently are selected from hydrogen, C1-12 alkyl, straight or branched C1-4 alkoxy, straight or branched C1-4 carboalkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, halo, nitro, or R3-R4 or R4-R5 independently form a benzene ring, provided that R2-R5 are not all hydrogen and R5 is not hydroxy; M is a pharmaceutically acceptable cation, C1-12 alkyl, straight or branched C1-4 acyl, or trialkylsilyl wherein the alkyl groups have from l to 6 carbon atoms.
9. The use of a compound of Formula I or II
I II
for inhibiting lipoxygenase activity in a human or lower animal, wherein R1 through R5 are independently selected from hydrogen, C1-C12 alkyl, straight or branched C1-4 alkoxy, straight or branched C1-4 carboalkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, nitro, hydroxy, a halogen, or where R1-R2, R3-R4, or R4-R5 form a benzene ring; and where M is a pharmaceutically acceptable cation, trialkyl silyl wherein the alkyl groups have 1 to 6 carbon atoms, C1-C12 alkyl, or straight or branched C1-4 acyl.
I II
for inhibiting lipoxygenase activity in a human or lower animal, wherein R1 through R5 are independently selected from hydrogen, C1-C12 alkyl, straight or branched C1-4 alkoxy, straight or branched C1-4 carboalkoxy, aryl selected from phenyl, 1-naphthyl or 2-naphthyl, nitro, hydroxy, a halogen, or where R1-R2, R3-R4, or R4-R5 form a benzene ring; and where M is a pharmaceutically acceptable cation, trialkyl silyl wherein the alkyl groups have 1 to 6 carbon atoms, C1-C12 alkyl, or straight or branched C1-4 acyl.
10. The use of a compound of Claim 1 for inhibiting lipoxygenase activity.
11. The use of a compound of Claim 2 for inhibiting the lipoxygenase activity.
12. The use of a compound of Claim 3 for inhibiting the lipoxygenase activity.
13. The use of a compound of Claim 4 for inhibiting the lipoxygenase activity.
14. The use of a compound of Claim 5 for inhibiting the lipoxygenase activity.
15. The use of a compound of Claim 6 for inhibiting the lipoxygenase activity.
16. The use of a compound of Claim 7 for inhibiting the lipoxygenase activity.
17. The use of a compound of Claim 8 for inhibiting the lipoxygenase activity.
18. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 1, in association with a pharmaceutically acceptable carrier.
19. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 2, in association with a pharmaceutically acceptable carrier.
20. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 3, in association with a pharmaceutically acceptable carrier.
21. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 4, in association with a pharmaceutically acceptable carrier.
22. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 5, in association with a pharmaceutically acceptable carrier.
23. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 6, in association with a pharmaceutically acceptable carrier.
24. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 7, in association with a pharmaceutically acceptable carrier.
25. A composition for inhibiting lipoxygenase activity, comprising an effective amount of a compound of Claim 8, in association with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US849,924 | 1977-11-09 | ||
| US06/849,924 US4761403A (en) | 1986-04-09 | 1986-04-09 | Lipoxygenase inhibiting compounds |
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| EP (1) | EP0240859B1 (en) |
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| US5260316A (en) * | 1991-07-30 | 1993-11-09 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5334600A (en) * | 1991-07-30 | 1994-08-02 | Ciba-Geigy Corporation | Isoquinolyl substituted hydroxylamine derivatives |
| US5350761A (en) * | 1991-07-30 | 1994-09-27 | Ciba-Geigy Corporation | Indolyl substituted hydroxylamine derivatives |
| ES2111059T3 (en) * | 1991-07-30 | 1998-03-01 | Ciba Geigy Ag | HYDROXYLAMINE DERIVATIVES SUBSTITUTED WITH HETEROARYL AS LIPOXIGENASE INHIBITORS. |
| GB9322828D0 (en) * | 1993-11-05 | 1993-12-22 | Sandoz Ltd | Organic compounds |
| GB9424842D0 (en) * | 1994-12-09 | 1995-02-08 | British Tech Group | Pharmaceutical compositions |
| US6268500B1 (en) * | 1997-01-31 | 2001-07-31 | Eli Lilly And Company | Separation of 5-nitroquinoline and 8-nitroquinoline |
| ATE394378T1 (en) * | 2000-01-11 | 2008-05-15 | Nycomed Gmbh | PHENANTHRIDINE -N- OXIDES |
| CA2330350A1 (en) | 2000-12-05 | 2002-06-05 | Chemokine Therapeutics Corporation | Therapeutics for chemokine mediated diseases |
| WO2002045702A2 (en) * | 2000-12-05 | 2002-06-13 | Chemokine Therapeutics Corporation | Tricyclic therapeutics for chemokine mediated diseases |
| MXPA04007611A (en) * | 2002-02-08 | 2005-05-27 | Hoffmann La Roche | Method of treating and preventing bone loss. |
| BRPI0519013A2 (en) * | 2004-12-13 | 2009-11-03 | Lilly Co Eli | single compound or stereoisomers, mixtures of pharmaceutically acceptable stereoisomers, salts, tautomers or prodrugs thereof, pharmaceutical composition, and use of a compound |
| FR2923826A1 (en) * | 2007-11-21 | 2009-05-22 | Ppg Sipsy Soc Par Actions Simp | PROCESS FOR THE SYNTHESIS OF 4-BENZOFURAN CARBOXYLIC ACID |
| CA2926950C (en) | 2013-10-10 | 2022-10-11 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase |
| CN109111401A (en) * | 2018-11-05 | 2019-01-01 | 南京金浩医药科技有限公司 | A kind of preparation method of 3- hydroxyl quinaldine -4- carboxylic acid |
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| US3264305A (en) * | 1963-09-16 | 1966-08-02 | Upjohn Co | 1-(2-alkenyloxy) carbostyrils |
| GB1185934A (en) * | 1967-06-28 | 1970-03-25 | Pfizer & Co C | Derivatives of 1,3(2H,4H)-Dioxoisoquinoline and preparation thereof |
| US3455931A (en) * | 1967-07-25 | 1969-07-15 | Smithkline Corp | N-aminoalkoxycarbostyrils |
| US3928612A (en) * | 1974-10-02 | 1975-12-23 | American Home Prod | 1,2-Dihydro- and 1,2,3,4-tetrahydro-1-oxo-3-isoquinolinecarboxylic acid derivatives as anti-allergic agents |
| US4283539A (en) * | 1979-12-18 | 1981-08-11 | Pfizer Inc. | Isoquinoline acetic acids |
| US4393075A (en) * | 1980-04-14 | 1983-07-12 | Takeda Chemical Industries, Ltd. | Quinone compounds and their use in suppressing the production of SRS-A in mammals |
| US4497827A (en) * | 1982-08-30 | 1985-02-05 | Syntex (U.S.A.) Inc. | Arachidonic acid analogues as anti-inflammatory and anti-allergic agents |
| JPH0613515B2 (en) * | 1983-03-14 | 1994-02-23 | 杏林製薬株式会社 | Pyrazolo [1,5-a] pyridine derivative and therapeutic agent containing the same |
| JPS59210021A (en) * | 1983-05-12 | 1984-11-28 | Kyowa Hakko Kogyo Co Ltd | Preventing and treating agent for disease caused by lipoxygenase metabolite |
| US4607053A (en) * | 1984-05-17 | 1986-08-19 | E. R. Squibb & Sons, Inc. | Arylhydroxamates useful as antiallergy agents |
-
1986
- 1986-04-09 US US06/849,924 patent/US4761403A/en not_active Expired - Lifetime
-
1987
- 1987-03-26 DE DE87104482T patent/DE3785600T2/en not_active Expired - Fee Related
- 1987-03-26 EP EP87104482A patent/EP0240859B1/en not_active Expired - Lifetime
- 1987-04-07 CA CA000534042A patent/CA1313376C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0240859B1 (en) | 1993-04-28 |
| DE3785600T2 (en) | 1993-11-04 |
| EP0240859A2 (en) | 1987-10-14 |
| EP0240859A3 (en) | 1989-08-02 |
| US4761403A (en) | 1988-08-02 |
| DE3785600D1 (en) | 1993-06-03 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |